PROJECT SUMMARY This proposal seeks to investigate striatal inflammation as a key predictor of brain reward circuitry dysfunction and anhedonia in patients with major depressive disorder (MDD) using simultaneous positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Anhedonia is a core feature of MDD and inflammation is hypothesized to be an important pathophysiologic factor in the etiology of anhedonia. Experimentally-induced inflammation and higher peripheral cytokine levels predict alterations in brain reward circuitry functioning, including decreased striatal response to reward and impaired dopaminergic functioning. However, no human imaging study to date has provided direct evidence that neuroinflammation is related to neural response to rewards and clinical symptoms of anhedonia. This represents a critical gap in understanding how inflammatory processes in the brain contribute to deficits in brain reward function and increased risk for anhedonia in MDD. Simultaneous PET-fMRI is suited to bridge this gap by directly measuring both neuroinflammation and functional neural responses to rewards. We propose to collect simultaneous PET- fMRI from unmedicated MDD patients with clinically significant anhedonia and matched healthy controls using the radioligand [18F]PBR111 to assess 18-kDa translocator protein (TSPO) expression, an index of neuroinflammation. We will evaluate group differences in striatal inflammation and frontostriatal activation to anticipation and receipt of rewards (Aim 1), correlations between PET-derived measures of striatal inflammation and fMRI-derived measures of frontostriatal activation to rewards in the MDD group (Aim 2), and correlations between PET-derived measures of striatal inflammation and anhedonia severity in the MDD group (Aim 3). Mentorship: Experts from UNC-Chapel Hill, Harvard, and Northwestern will mentor the candidate: Gabriel Dichter, Ph.D., will guide overall professional development and provide training in functional neuroimaging and the neurobiology of anhedonia; David Lalush, Ph.D., will provide conceptual and methodological training in simultaneous PET-fMRI imaging; Susan Girdler, Ph.D., will mentor in broader career development and provides expertise in mood disorders; Young Truong, Ph.D. contributes expertise in neuroimaging statistics; Jacob Hooker, Ph.D. and Diego Pizzagalli, Ph.D., provide practical PET-fMRI training opportunities with diverse designs and clinical samples; Gregory Miller, Ph.D., Robin Nusslock, Ph.D., and Keely Muscatell, Ph.D., contribute expertise and training in psychoneuroimmunology. Career Development: This award provides the necessary training to become an expert in the neurobiology of anhedonia and multi-modal imaging and the experience to succeed as an independent research scientist. Career Goals: This is the first step in a program of research that seeks to use simultaneous PET-fMRI to investigate neuroinflammatory mechanisms of anhedonia across psychiatric disorders and to identify novel neuroimmune treatment targets for future experimental therapeutics clinical trials.